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Appendix A
NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE
Health Technology Appraisal
Donepezil, galantamine, rivastigmine and memantine for the treatment
of mild to moderate Alzheimer's disease
(Part review of TA 111)
Draft scope
Appraisal objective 1
To review and update as necessary guidance to the NHS in England and
Wales 2 on the clinical and cost effectiveness of donepezil, galantamine,
rivastigmine and memantine within their licensed indications for the treatment
of mild to moderate Alzheimer’s disease which was issued in November 2006
(amended September 2007, August 2009).
Background
Dementia is a chronic progressive mental disorder that adversely affects
higher cortical functions including memory, thinking and orientation.
Alzheimer’s disease is the most common form of dementia. It is a
degenerative cerebral disease with characteristic neuropathological and
neurochemical features. Alzheimer’s disease is usually insidious in onset and
develops slowly but steadily over a period of several years. It affects
predominantly the elderly. Progression is characterised by deterioration in
cognition (thinking, conceiving, reasoning) and functional ability (activities of
daily living) and a disturbance in behaviour and mood. Changes in one or
more of these domains and their effects on the person provide the basis for
diagnosis and they are used to assess the severity and progression of the
condition.
Population data (2002) for England and Wales show an estimated prevalence
of 290,000 people with Alzheimer’s disease. The incidence rate for
1
The Department of Health’s remits to the Institute are:
As part of the planned review of guidance on treatment of Alzheimer’s disease: to appraise the clinical
and cost effectiveness of memantine (Ebixa) for treatment of moderate Alzheimer’s disease.
To appraise the clinical and cost effectiveness of medicines which are licensed, at the time NICE
prepares its appraisal consultation document, for treatment of severe Alzheimer's disease, including
memantine and cholinesterase inhibitors.
The comparison should be in each case between drug therapy (in combination with supportive care) and
current treatment alternatives (including best supportive care alone).
2
NICE Technology Appraisal Guidance No 111 - Donepezil, galantamine, rivastigmine (review) and
memantine for the treatment of Alzheimer’s disease (amended) (November 2006, amended September
2007, August 2009)
National Institute for Health and Clinical Excellence
Draft scope for the appraisal of donepezil, galantamine, rivastigmine & memantine for the
treatment of mild to moderate Alzheimer's disease
Issue Date: September 2009
Page 1 of 9
Appendix A
Alzheimer’s disease in people over the age of 65 years has been estimated at
4.9 per 1000 person-years in the UK.
People with Alzheimer’s disease lose the ability to carry out routine daily
activities like dressing, toileting, travelling and handling money and, as a
result, many people require a high level of care. Often, this is provided by an
elderly relative, whose own health and quality of life can be affected by the
burden of providing care. Behavioural changes in the person, such as
aggression, are particularly disturbing for carers.
Several different methods are used to assess the severity of Alzheimer’s
disease. These include: the Clinical Global Impression of Change (CGIC);
Clinician’s Interview-based Impression of Change (CIBIC) and CIBIC-plus for
global outcomes; the Global deterioration scale (GD) and the Progressive
Deterioration Scale (PDS) for functional/quality-of-life scales; and the
Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog – 70
points) or the MMSE (Mini Mental State Examination) (30 points) for cognitive
outcomes. MMSE score, for example, denotes the severity of cognitive
impairment as follows: mild Alzheimer’s disease: MMSE 21–26, moderate
Alzheimer’s disease: MMSE 10–20, moderately severe Alzheimer’s disease:
MMSE 10–14, severe Alzheimer’s disease: MMSE less than 10.
Management of Alzheimer's disease involves treatment of cognitive,
behavioural and psychological symptoms. Non-pharmacological treatment is
social support and increasing assistance with day-to-day activities. These
include: information and education, carer support groups, community
dementia teams; home nursing and personal care, community services such
as meals-on-wheels, sitter services, day centres, respite care and care
homes.
NICE guidance (Technology Appraisal 111 [see appendix] and Clinical
Guideline 42) recommends the three acetylcholinesterase (AChE) inhibitors
donepezil, galantamine and rivastigmine as options in the management of
patients with Alzheimer’s disease of moderate severity only (for people with a
MMSE score of between 10 and 20 points).Treatment with
acetylcholinesterase inhibitors is initiated by specialists in the care of patients
with dementia (that is, psychiatrists including those specialising in learning
disability, neurologists, and physicians specialising in the care of the elderly),
who seek carers’ views on the patient’s condition at baseline. Patients
maintained on treatment with AChE inhibitors are reviewed every 6 months by
MMSE score and global, functional and behavioural assessment. Treatment is
discontinued when patient’s MMSE score falls below 10 points. Memantine is
not recommended as a treatment option for people with moderately severe to
severe Alzheimer’s disease except as part of well designed clinical studies.
The technologies
Donepezil (Aricept, Eisai), rivastigmine (Exelon, Novartis), and galantamine
(Reminyl, Shire) are AChE inhibitors, which work by increasing the
concentration of acetylcholine at sites of neurotransmission. Donepezil,
National Institute for Health and Clinical Excellence
Draft scope for the appraisal of donepezil, galantamine, rivastigmine & memantine for the
treatment of mild to moderate Alzheimer's disease
Issue Date: September 2009
Page 2 of 9
Appendix A
rivastigmine and galantamine have marketing authorizations in the UK for the
treatment of adults with mild to moderately severe Alzheimer’s dementia.
Memantine (Ebixa, Lundbeck) is a voltage-dependent, moderate-affinity,
uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that blocks
the effects of pathologically elevated tonic levels of glutamate that may lead to
neuronal dysfunction. It is has a UK marketing authorisation for the treatment
of people with moderate to severe Alzheimer’s disease.
Intervention(s)
•
Donepezil
•
Galantamine
•
Rivastigmine
•
Memantine
Population(s)
Adults with mild to moderate Alzheimer’s disease
Comparators
For people with mild disease:
•
Treatment without acetylcholinesterase
inhibitors (nor memantine)
For people with moderate disease:
•
Donepezil
•
Galantamine
•
Rivastigmine
•
Memantine
•
Treatment without acetylcholinesterase
inhibitors
National Institute for Health and Clinical Excellence
Draft scope for the appraisal of donepezil, galantamine, rivastigmine & memantine for the
treatment of mild to moderate Alzheimer's disease
Issue Date: September 2009
Page 3 of 9
Appendix A
Outcomes
The outcome measures to be considered include:
•
Measures of severity and response to treatment
including the following methods of assessment:
o Alzheimer's Disease Assessment Scalecognitive subscale (ADAS-cog)
o Progressive Deterioration Scale (PDS)
o Global deterioration scale (GD)
o Clinical Global Impression of Change
(CGIC)
o Clinician Interview-Based Impression of
Change (CIBIC and CIBIC-plus)
o Mini Mental State Examination (MMSE)
Economic analysis
•
behavioural symptoms (e.g. neuropsychiatric
inventory, NPI)
•
mortality
•
ability to remain independent
•
likelihood of admission to residential/nursing
care
•
health related quality of life of patients and
carers (analyses should be carried out
separately for patients alone, and for patients
and carers combined)
•
adverse effects of treatment
The reference case stipulates that the cost
effectiveness of treatments should be expressed in
terms of incremental cost per quality-adjusted life year.
The reference case stipulates that the time horizon for
estimating clinical and cost effectiveness should be
sufficiently long to reflect any differences in costs or
outcomes between the technologies being compared.
Costs will be considered from an NHS and Personal
Social Services perspective.
National Institute for Health and Clinical Excellence
Draft scope for the appraisal of donepezil, galantamine, rivastigmine & memantine for the
treatment of mild to moderate Alzheimer's disease
Issue Date: September 2009
Page 4 of 9
Appendix A
Other
considerations
Guidance will only be issued in accordance with the
marketing authorisation
If evidence allows, interventions will be compared with
each other within their licensed indications.
Treatment without acetylcholinesterase inhibitors nor
memantine is considered to be social support and
assistance with day-to-day activities. These include:
information and education, carer support groups,
community dementia teams; home nursing and
personal care, community services such as meals-onwheels, sitter services, day centres, respite care and
care homes.
Related NICE
recommendations
Related Technology Appraisals:
NICE Technology Appraisal Guidance No 111 Donepezil, galantamine, rivastigmine (review) and
memantine for the treatment of Alzheimer’s disease
(amended) (November 2006, amended September
2007, August 2009)
Related Guidelines:
Clinical Guideline No 42, November 2006, ‘Dementia:
supporting people with dementia and their carers in
health and social care’.
Questions for consultation
Have the most appropriate comparators for the treatment of mild to moderate
Alzheimer’s disease been included in the scope?
Are there any subgroups of patients in whom the technology is expected to be
more clinically effective and cost effective or other groups that should be
examined separately?
Are there any issues that require special attention in light of the duty to have
due regard to the need to eliminate unlawful discrimination and promote
equality?
NICE intends to appraise this technology through its Multiple Technology
Appraisal (MTA) Process. We welcome comments on the appropriateness of
appraising this topic through this process. (Information on the Institute’s
Technology Appraisal processes is available at
http://www.nice.org.uk/aboutnice/howwework/devnicetech/technologyappraisa
lprocessguides/technology_appraisal_process_guides.jsp)
National Institute for Health and Clinical Excellence
Draft scope for the appraisal of donepezil, galantamine, rivastigmine & memantine for the
treatment of mild to moderate Alzheimer's disease
Issue Date: September 2009
Page 5 of 9
Appendix A
Note for consultation
NICE will be consulting on a review proposal for appraising the clinical and
cost effectiveness of memantine for the treatment of severe Alzheimer’s
disease.
National Institute for Health and Clinical Excellence
Draft scope for the appraisal of donepezil, galantamine, rivastigmine & memantine for the
treatment of mild to moderate Alzheimer's disease
Issue Date: September 2009
Page 6 of 9
Appendix A
Appendix: Current NICE Guidance (TA 111)
1
Guidance
This guidance applies to donepezil, galantamine, rivastigmine and
memantine within the marketing authorisations held for each drug
at the time of this appraisal; that is:
• donepezil, galantamine, rivastigmine for mild to moderately
severe Alzheimer’s disease
• memantine for moderately severe to severe Alzheimer’s
disease.
The benefits of these drugs for patients with other forms of
dementia (for example, vascular dementia or dementia with Lewy
bodies) have not been assessed in this guidance.
1.1
The three acetylcholinesterase inhibitors donepezil, galantamine
and rivastigmine are recommended as options in the management
of patients with Alzheimer’s disease of moderate severity only (that
is, subject to section 1.2 below, those with a Mini Mental State
Examination [MMSE] score of between 10 and 20 points), and
under the following conditions:
• Only specialists in the care of patients with dementia (that is,
psychiatrists including those specialising in learning disability,
neurologists, and physicians specialising in the care of the
elderly) should initiate treatment. Carers’ views on the patient’s
condition at baseline should be sought.
• Patients who continue on the drug should be reviewed every
6 months by MMSE score and global, functional and behavioural
assessment. Carers’ views on the patient’s condition at follow-up
should be sought. The drug should only be continued while the
patient’s MMSE score remains at or above 10 points (subject to
National Institute for Health and Clinical Excellence
Draft scope for the appraisal of donepezil, galantamine, rivastigmine & memantine for the
treatment of mild to moderate Alzheimer's disease
Issue Date: September 2009
Page 7 of 9
Appendix A
section 1.2 below) and their global, functional and behavioural
condition remains at a level where the drug is considered to be
having a worthwhile effect. Any review involving MMSE
assessment should be undertaken by an appropriate specialist
team, unless there are locally agreed protocols for shared care.
When using the MMSE to diagnose moderate Alzheimer’s disease,
clinicians should be mindful of the need to secure equality of
access to treatment for patients from different ethnic groups (in
particular those from different cultural backgrounds) and patients
with disabilities.
1.2
In determining whether a patient has Alzheimer’s disease of
moderate severity for the purposes of section 1.1 above,
healthcare professionals should not rely, or rely solely, upon the
patient’s MMSE score in circumstances where it would be
inappropriate to do so. These are:
• where the MMSE is not, or is not by itself, a clinically appropriate
tool for assessing the severity of that patient’s dementia because
of the patient’s learning or other disabilities (for example,
sensory impairments) or linguistic or other communication
difficulties or
• where it is not possible to apply the MMSE in a language in
which the patient is sufficiently fluent for it to be an appropriate
tool for assessing the severity of dementia, or there are similarly
exceptional reasons why use of the MMSE, or use of the MMSE
by itself, would be an inappropriate tool for assessing the
severity of dementia in that individual patient’s case.
In such cases healthcare professionals should determine whether
the patient has Alzheimer’s disease of moderate severity by
making use of another appropriate method of assessment. For the
avoidance of any doubt, the acetylcholinesterase inhibitors are
National Institute for Health and Clinical Excellence
Draft scope for the appraisal of donepezil, galantamine, rivastigmine & memantine for the
treatment of mild to moderate Alzheimer's disease
Issue Date: September 2009
Page 8 of 9
Appendix A
recommended as options in the management of people assessed
on this basis as having Alzheimer’s disease of moderate severity.
The same approach should apply in determining for the purposes
of section 1.1 above, and in the context of a decision whether to
continue the use of the drug, whether the severity of the patient’s
dementia has increased to a level which in the general population
of Alzheimer’s disease patients would be marked by an MMSE
score below 10 points.
1.3
When the decision has been made to prescribe an
acetylcholinesterase inhibitor, it is recommended that therapy
should be initiated with a drug with the lowest acquisition cost
(taking into account required daily dose and the price per dose
once shared care has started). However, an alternative
acetylcholinesterase inhibitor could be prescribed where it is
considered appropriate having regard to adverse event profile,
expectations around concordance, medical comorbidity, possibility
of drug interactions and dosing profiles.
1.4
Memantine is not recommended as a treatment option for patients
with moderately severe to severe Alzheimer’s disease except as
part of well-designed clinical studies.
1.5
Patients with mild Alzheimer’s disease who are currently receiving
donepezil, galantamine or rivastigmine, and patients with
moderately severe to severe Alzheimer’s disease currently
receiving memantine, whether as routine therapy or as part of a
clinical trial, may be continued on therapy (including after the
conclusion of a clinical trial) until they, their carers and/or specialist
consider it appropriate to stop.
National Institute for Health and Clinical Excellence
Draft scope for the appraisal of donepezil, galantamine, rivastigmine & memantine for the
treatment of mild to moderate Alzheimer's disease
Issue Date: September 2009
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